Abstract
A number of studies have suggested that the active derivative of vitamin A, retinoic acid (RA), may be important for early development of mammalian embryos. Severe vitamin A deprivation in rodents results in maternal infertility, precluding a thorough investigation of the role of RA during embryogenesis. Here we show that production of RA by the retinaldehyde dehydrogenase-2 (Raldh2) enzyme is required for mouse embryo survival and early morphogenesis. Raldh2 is an NAD-dependent aldehyde dehydrogenase with high substrate specificity for retinaldehyde. Its pattern of expression during mouse development has suggested that it may be responsible for embryonic RA synthesis. We generated a targeted disruption of the mouse Raldh2 gene and found that Raldh2-/- embryos, which die at midgestation without undergoing axial rotation (body turning), exhibit shortening along the anterioposterior axis and do not form limb buds. Their heart consists of a single, medial, dilated cavity. Their frontonasal region is truncated and their otocysts are severely reduced. These defects result from a block in embryonic RA synthesis, as shown by the lack of activity of RA-responsive transgenes, the altered expression of an RA-target homeobox gene and the near full rescue of the mutant phenotype by maternal RA administration. Our data establish that RA synthesized by the post-implantation mammalian embryo is an essential developmental hormone whose lack leads to early embryo death.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Abnormalities, Multiple / genetics
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Aldehyde Oxidoreductases / genetics*
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Aldehyde Oxidoreductases / metabolism*
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Animals
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Basic Helix-Loop-Helix Transcription Factors
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Embryo, Mammalian / abnormalities
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Embryo, Mammalian / metabolism
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Embryo, Mammalian / pathology
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Embryonic Development / physiology*
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Embryonic and Fetal Development / drug effects
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Embryonic and Fetal Development / physiology*
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Female
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Fibroblast Growth Factor 10
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Fibroblast Growth Factor 3
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Fibroblast Growth Factor 8
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Fibroblast Growth Factors / genetics
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Fibroblast Growth Factors / metabolism
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Gene Expression Regulation, Developmental*
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Limb Buds / abnormalities
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Male
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Mice
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Mice, Inbred Strains
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Mice, Mutant Strains
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Mice, Transgenic
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Otx Transcription Factors
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Pregnancy
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Response Elements
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Retinal Dehydrogenase
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Trans-Activators / genetics
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Trans-Activators / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transgenes
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Tretinoin / metabolism*
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Tretinoin / pharmacology
Substances
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Basic Helix-Loop-Helix Transcription Factors
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DNA-Binding Proteins
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Fgf3 protein, mouse
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Fgf8 protein, mouse
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Fibroblast Growth Factor 10
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Fibroblast Growth Factor 3
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Hand1 protein, mouse
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Homeodomain Proteins
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Nerve Tissue Proteins
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Otx Transcription Factors
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Proto-Oncogene Proteins
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Trans-Activators
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Transcription Factors
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helix-loop-helix protein, eHAND
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homeobox A1 protein
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Fibroblast Growth Factor 8
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Tretinoin
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Fibroblast Growth Factors
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Aldehyde Oxidoreductases
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Retinal Dehydrogenase